期刊文献

Identification of the modulatory Ca²⁺-binding sites of acid-sensing ion channel 1a 收藏

鉴定调节性Ca ²⁺ - 酸性离子通道1a的结合位点

原文求助发布源

作者

Ophélie Molton[1];Olivier Bignucolo[2];Stephan Kellenberger[3];Ophélie Molton[1];Olivier Bignucolo[2];Stephan Kellenberger[3]

作者单位

[1]Department of Biomedical Sciences, University of Lausanne, 1011 Lausanne, Switzerland Contribution: Conceptualization, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing;[2]Swiss Institute of Bioinformatics, 4056 Basel, Switzerland Contribution: Conceptualization, Investigation, Methodology, Writing – original draft, Writing – review and editing;[3]Department of Biomedical Sciences, University of Lausanne, 1011 Lausanne, Switzerland

关键词

acid-sensing ion channel; ion channel; activation; pH dependence; molecular dynamics simulations

关键词译文

酸性离子通道；离子通道；激活;pH依赖；分子动力学模拟

发布日期

19 June 2024

DOI

10.1098/rsob.240028

来源信息

Open Biology ISSN：e2046-2441, 2024年, 14卷, 6期

摘要

Acid-sensing ion channels (ASICs) are neuronal Na⁺-permeable ion channels activated by extracellular acidification. ASICs are involved in learning, fear sensing, pain sensation and neurodegeneration. Increasing the extracellular Ca²⁺ concentration decreases the H⁺ sensitivity of ASIC1a, suggesting a competition for binding sites between H⁺ and Ca²⁺ ions. Here, we predicted candidate residues for Ca²⁺ binding on ASIC1a, based on available structural information and our molecular dynamics simulations. With functional measurements, we identified several residues in cavities previously associated with pH-dependent gating, whose mutation reduced the modulation by extracellular Ca²⁺ of the ASIC1a pH dependence of activation and desensitization. This occurred probably owing to a disruption of Ca²⁺ binding. Our results link one of the two predicted Ca²⁺-binding sites in each ASIC1a acidic pocket to the modulation of channel activation. Mg²⁺ regulates ASICs in a similar way as does Ca²⁺. We show that Mg²⁺ shares some of the binding sites with Ca²⁺. Finally, we provide evidence that some of the ASIC1a Ca²⁺-binding sites are functionally conserved in the splice variant ASIC1b. Our identification of divalent cation-binding sites in ASIC1a shows how Ca²⁺ affects ASIC1a gating, elucidating a regulatory mechanism present in many ion channels.

摘要译文

酸性离子通道（ASIC）是神经元Na ⁺ - 可渗透的离子通道通过细胞外酸化激活。ASIC参与学习，恐惧感应，疼痛感和神经退行性。增加细胞外Ca ²⁺浓度降低了ASIC1A的H ⁺敏感性，这表明H ⁺和Ca ^{之间的结合位点竞争2+}离子。在这里，我们预测了基于可用的结构信息和我们的分子动力学模拟，CA ²⁺结合了ASIC1A的候选残基。通过功能测量，我们确定了先前与pH依赖性门的腔体中的几个残基，它们的突变减少了ASIC1A pH依赖性和脱敏的细胞外Ca ²⁺的调节。这可能是由于CA ²⁺结合的破坏。我们的结果将每个ASIC1A酸性袋中的两个预测的CA ²⁺结合位点与通道激活的调节联系起来。mg ²⁺以与Ca ²⁺相似的方式调节ASIC。我们表明Mg ²⁺与CA ²⁺共享一些绑定位点。最后，我们提供了证据表明，某些ASIC1A CA ²⁺结合位点在剪接变体ASIC1B中是功能保守的。我们对ASIC1A中二价阳离子结合位点的鉴定显示了CA ²⁺如何影响ASIC1A门控，从而阐明了许多离子通道中存在的调节机制。

Ophélie Molton[1];Olivier Bignucolo[2];Stephan Kellenberger[3];Ophélie Molton[1];Olivier Bignucolo[2];Stephan Kellenberger[3]. Identification of the modulatory Ca²⁺-binding sites of acid-sensing ion channel 1a[J]. Open Biology, 2024,14(6)

Identification of the modulatory Ca2+-binding sites of acid-sensing ion channel 1a 收藏

Identification of the modulatory Ca²⁺-binding sites of acid-sensing ion channel 1a 收藏